tbuckley/cabot-search huggingface dataset:
Good Habits Do Not Necessarily Help Childhood Constipation—Reply
Authors: Lynsey R. Zuar, Lindsay A. Thompson
Journal: JAMA Pediatrics (2023)

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Converging on a Cure: The Roads to Predictive Immunotherapy
Authors: Genevieve L. Stein-O'Brien, Dung T. Le, Elizabeth M. Jaffee, Elana J. Fertig, Neeha Zaidi
Journal: Cancer Discovery (2023)

Summary: Convergence science teams integrating clinical, biological, engineering, and computational expertise are inventing new forecast systems to monitor and predict evolutionary changes in tumor and immune interactions during early cancer progression and therapeutic response. The resulting methods should inform a new predictive medicine paradigm to select adaptive immunotherapeutic regimens personalized to patients’ tumors at a given time during their cancer progression for durable patient response.
External validation of a novel electronic risk score for cancer‐associated thrombosis in a comprehensive cancer center
Authors: Ang Li, Giordana De Las Pozas, Clark R. Andersen, Chijioke C. Nze, Katy M. Toale, Emily M. Milner, Nathanael R. Fillmore, Elizabeth Yu Chiao, Cristhiam Rojas Hernandez, Michael H. Kroll, Kelly W. Merriman, Christopher R. Flowers
Journal: American Journal of Hematology (2023)

Abstract Venous thromboembolism (VTE) is a significant complication for cancer patients undergoing systemic therapy. We performed an independent external validation for a recently derived and validated a novel electronic health record (EHR) VTE risk score in a comprehensive cancer center. Adult patients with incident cancer diagnoses were identified from MD Anderson Cancer Center Tumor Registry 1/2017–1/2021. Baseline covariates extracted at the time of first‐line systemic therapy included demographics, cancer site/histology, stage, treatment, complete blood count, body mass index, recent prolonged hospitalization, and history of VTE or paralysis. VTE was ascertained using an institution‐specific natural language processing radiology algorithm (positive predictive value of 94.8%). The median follow‐up for 21 142 cancer patients was 8.1 months. There were 1067 (5.7%) VTE within 6 months after systemic therapy. The distribution of the novel score for 0‐, 1, 2, 3, 4, 5+ was 5661, 3558, 3462, 3489, 2918, and 2054; while the corresponding 6‐month VTE incidence was 1.3%, 3.1%, 5.4%, 7.3%, 9.3%, and 13.8%, respectively (c statistic 0.71 [95% CI 0.69–0.72] with excellent calibration). In comparison, the Khorana score had a c statistic of 0.64 [95% CI 0.62–0.65]. The two risk scores had 80% concordance; the novel score reclassified 20% of Khorana score (3530 low‐to‐high with 9.0% VTE; 734 high‐to‐low with 3.4% VTE) and led to a 25% increment in VTEs captured in the high‐risk group. In conclusion, the novel score demonstrated consistent discrimination and calibration across cohorts with heterogenous demographics. It could become a new standard to select high‐risk populations for clinical trials and VTE monitoring.
Clinical Relevance of <i>BRCA1</i> Promoter Methylation Testing in Patients with Ovarian Cancer
Authors: Félix Blanc-Durand, Roseline Tang, Margaux Pommier, Marzieh Nashvi, Sophie Cotteret, Catherine Genestie, Audrey Le Formal, Patricia Pautier, Judith Michels, Maria Kfoury, Robert Hervé, Sylvie Mengue, Estelle Wafo, Antoine Elies, Gregoire Miailhe, Jennifer Uzan, Etienne Rouleau, Alexandra Leary
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Homologous recombination deficiency (HRD) is closely related to PARP inhibitor (PARPi) benefit in ovarian cancer. The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade ovarian cancer to HRD status and clinical behavior to assess its clinical relevance. Experimental Design: This is a retrospective monocentric analysis of patients centrally tested for genomic instability score (GIS) by MyChoice CDx (Myriad Genetics). The detection of BRCA1 promoter methylation and quantification of methylation levels were performed by quantitative droplet digital PCR methodology. High BRCA1 methylation was defined as ≥70% and deemed to be associated with homozygous silencing. Results: Of 100 patients, 11% harbored a deleterious BRCA1/2 mutation. GIS was considered positive (score ≥ 42) for 52 patients and negative for 48 patients. Using a 70% cutoff, 19% (15/79) of BRCA wild-type ovarian cancer had high BRCA1 methylation levels. All of the highly methylated tumors were classified as HRD, achieving a positive predictive value of 100%. We detected 14% (11/79) low-methylated tumors (1%–69%), and all of them were also classified as HRD. Mean GIS was 61.5 for BRCAmut, 66.4 for high-BRCAmeth, 58.9 for low-BRCAmeth, and 33.3 for BRCAwt unmethylated (P &amp;lt; 0.001). Low methylation levels detected in samples previously exposed to chemotherapy appeared to be associated with poor outcome post-platinum. Conclusions: Patients with ovarian cancer with high levels of BRCA1 hypermethylation are very likely to have high GIS and therefore represent good candidates for PARPi treatment. These results may be highly relevant to other tumor types for HRD prediction. See related commentary by Garg and Oza, p. 2957
Impact of multimorbidity on mortality in heart failure with reduced ejection fraction: which comorbidities matter most? An analysis of <scp>PARADIGM‐HF</scp> and <scp>ATMOSPHERE</scp>
Authors: Pooja Dewan, João Pedro Ferreira, Jawad H. Butt, Mark C. Petrie, William T. Abraham, Akshay S. Desai, Kenneth Dickstein, Lars Køber, Milton Packer, Jean L. Rouleau, Simon Stewart, Karl Swedberg, Michael R. Zile, Scott D. Solomon, Pardeep S. Jhund, John J.V. McMurray
Journal: European Journal of Heart Failure (2023)
Transmembrane protein 232 regulates inflammation in experimental models of atopic dermatitis
Authors: Hakim Ben Abdallah, Claus Johansen
Journal: British Journal of Dermatology (2023)

Atopic dermatitis (AD) is a prevalent inflammatory skin disorder characterized by dry and itchy skin that may significantly impair a patient’s quality of life.1,2 The ongoing progress of molecular insights into the mechanisms underlying AD has advanced our understanding, revealing important signalling pathways and novel potential targets paving the way for the expanding drug development.3 Interestingly, recent genetic association studies identified TMEM232 to be associated with atopic dermatitis in Asian populations, suggesting it may be implicated in the mechanisms of AD.4–6 Yet, the function of transmembrane protein 232 (TMEM232) has remained unexplored until now. In this issue of the BJD, Han et al. report novel findings using in vitro (human keratinocytes stimulated with different cytokines) and in vivo (mice challenged with MC903) experimental models mimicking AD, demonstrating that TMEM232 may be involved in the dysregulated immune response in AD.7 To explore the role of TMEM232 in regulating inflammation, Tmem232 was knocked down (i.e. reduced gene expression) by short hairpin RNA or overexpressed using a plasmid construct in human keratinocyte cell lines (HaCaT). Interestingly, Tmem232 knockdown markedly decreased proinflammatory cytokine production under tumour necrosis factor/interferon-γ stimulation, whereas Tmem232 overexpression increased proinflammatory cytokine production in unstimulated cells. In line with this, TMEM232 levels were significantly upregulated in the lesional skin of patients with AD compared with healthy donors. These findings provide evidence that TMEM232 may have a significant function in regulating inflammation in AD.
Opportunities for Achieving the Cancer Moonshot Goal of a 50% Reduction in Cancer Mortality by 2047
Authors: Meredith S. Shiels, Stanley Lipkowitz, Nicole G. Campos, Mark Schiffman, John T. Schiller, Neal D. Freedman, Amy Berrington de González
Journal: Cancer Discovery (2023)

Abstract On February 2, 2022, President Biden and First Lady Dr. Biden reignited the Cancer Moonshot, setting a new goal to reduce age-standardized cancer mortality rates by at least 50% over the next 25 years in the United States. We estimated trends in U.S. cancer mortality during 2000 to 2019 for all cancers and the six leading types (lung, colorectum, pancreas, breast, prostate, liver). Cancer death rates overall declined by 1.4% per year from 2000 to 2015, accelerating to 2.3% per year during 2016 to 2019, driven by strong declines in lung cancer mortality (−4.7%/year, 2014 to 2019). Recent declines in colorectal (−2.0%/year, 2010–2019) and breast cancer death rates (−1.2%/year, 2013–2019) also contributed. However, trends for other cancer types were less promising. To achieve the Moonshot goal, progress against lung, colorectal, and breast cancer deaths needs to be maintained and/or accelerated, and new strategies for prostate, liver, pancreatic, and other cancers are needed. We reviewed opportunities to prevent, detect, and treat these common cancers that could further reduce population-level cancer death rates and also reduce disparities. Significance: We reviewed opportunities to prevent, detect, and treat common cancers, and show that to achieve the Moonshot goal, progress against lung, colorectal, and breast cancer deaths needs to be maintained and/or accelerated, and new strategies for prostate, liver, pancreatic, and other cancers are needed. See related commentary by Bertagnolli et al., p. 1049. This article is highlighted in the In This Issue feature, p. 1027
<i>SOX17</i> Enhancer Variants Disrupt Transcription Factor Binding And Enhancer Inactivity Drives Pulmonary Hypertension
Authors: Rachel Walters, Eleni Vasilaki, Jurjan Aman, Chien-Nien Chen, Yukyee Wu, Olin D. Liang, Ali Ashek, Olivier Dubois, Lin Zhao, Farah Sabrin, Inês Cebola, Jorge Ferrer, Nicholas W. Morrell, James R. Klinger, Martin R. Wilkins, Lan Zhao, Christopher J. Rhodes
Journal: Circulation (2023)

Background: Pulmonary arterial hypertension (PAH) is a rare disease characterized by remodeling of the pulmonary arteries, increased vascular resistance, and right-sided heart failure. Genome-wide association studies of idiopathic/heritable PAH established novel genetic risk variants, including conserved enhancers upstream of transcription factor (TF) SOX17 containing 2 independent signals. SOX17 is an important TF in embryonic development and in the homeostasis of pulmonary artery endothelial cells (hPAEC) in the adult. Rare pathogenic mutations in SOX17 cause heritable PAH. We hypothesized that PAH risk alleles in an enhancer region impair TF-binding upstream of SOX17 , which in turn reduces SOX17 expression and contributes to disturbed endothelial cell function and PAH development. Methods: CRISPR manipulation and siRNA were used to modulate SOX17 expression. Electromobility shift assays were used to confirm in silico – predicted TF differential binding to the SOX17 variants. Functional assays in hPAECs were used to establish the biological consequences of SOX17 loss. In silico analysis with the connectivity map was used to predict compounds that rescue disturbed SOX17 signaling. Mice with deletion of the SOX17 -signal 1 enhancer region ( SOX17 -4593/enhKO) were phenotyped in response to chronic hypoxia and SU5416/hypoxia. Results: CRISPR inhibition of SOX17 -signal 2 and deletion of SOX17 -signal 1 specifically decreased SOX17 expression. Electromobility shift assays demonstrated differential binding of hPAEC nuclear proteins to the risk and nonrisk alleles from both SOX17 signals. Candidate TFs HOXA5 and ROR-α were identified through in silico analysis and antibody electromobility shift assays. Analysis of the hPAEC transcriptomes revealed alteration of PAH-relevant pathways on SOX17 silencing, including extracellular matrix regulation. SOX17 silencing in hPAECs resulted in increased apoptosis, proliferation, and disturbance of barrier function. With the use of the connectivity map, compounds were identified that reversed the SOX17-dysfunction transcriptomic signatures in hPAECs. SOX17 enhancer knockout in mice reduced lung SOX17 expression, resulting in more severe pulmonary vascular leak and hypoxia or SU5416/hypoxia-induced pulmonary hypertension. Conclusions: Common PAH risk variants upstream of the SOX17 promoter reduce endothelial SOX17 expression, at least in part, through differential binding of HOXA5 and ROR-α. Reduced SOX17 expression results in disturbed hPAEC function and PAH. Existing drug compounds can reverse the disturbed SOX17 pulmonary endothelial transcriptomic signature.
Effects of Individual Amino Acids on the Blood Circulation of Biosynthetic Protein Nanocages: Toward Guidance on Surface Engineering
Authors: Ao Liang, Wei Zhou, Hui Zhang, Juan Zhang, Xian‐En Zhang, Ti Fang, Feng Li
Journal: Advanced Healthcare Materials (2023)

Protein nanocages (PNCs) hold great promise for developing multifunctional nanomedicines. Long blood circulation is a key requirement of PNCs for most in vivo application scenarios. In addition to the classical PEGylation strategy, short peptides with a specific sequence screened via phage display are also very effective in prolonging the blood half-life (t1/2 ) of PNCs. However, there is a lack of knowledge on how individual amino acids affect the circulation of PNCs. Here the effects of the 20 proteinogenic amino acids in the form of an X3 or X5 tag (X represents an amino acid) are explored on the pharmacokinetics of PNCs, which lead to the formation of a heatmap illustrating the extent of t1/2 prolongation by each proteinogenic amino acid. Significantly, oligo-lysine and oligo-arginine can effectively prolong the t1/2 of strongly negatively charged PNCs through charge neutralization, while oligo-cysteine can also do so, but via a different mechanism, mediating the covalent binding of PNCs with plasma albumin as a stealth material. These findings are extendible and offer guidance for surface-engineering biosynthetic PNCs and other nanoparticles.
METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL
Authors: Yiming Wu, Meiling Jin, Mike Fernandez, Kevyn L. Hart, Aijun Liao, Xinzhou Ge, Stacey M. Fernandes, Tinisha McDonald, Zhenhua Chen, Daniel Röth, Lucy Y. Ghoda, Guido Marcucci, Markus Kalkum, Raju K. Pillai, Alexey V. Danilov, Jingyi Jessica Li, Jianjun Chen, Jennifer R. Brown, Steven T. Rosen, Tanya Siddiqi, Lili Wang
Journal: Blood Cancer Discovery (2023)

RNA splicing dysregulation underlies the onset and progression of cancers. In chronic lymphocytic leukemia (CLL), spliceosome mutations leading to aberrant splicing occur in ∼20% of patients. However, the mechanism for splicing defects in spliceosome-unmutated CLL cases remains elusive. Through an integrative transcriptomic and proteomic analysis, we discover that proteins involved in RNA splicing are posttranscriptionally upregulated in CLL cells, resulting in splicing dysregulation. The abundance of splicing complexes is an independent risk factor for poor prognosis. Moreover, increased splicing factor expression is highly correlated with the abundance of METTL3, an RNA methyltransferase that deposits N6-methyladenosine (m6A) on mRNA. METTL3 is essential for cell growth in vitro and in vivo and controls splicing factor protein expression in a methyltransferase-dependent manner through m6A modification-mediated ribosome recycling and decoding. Our results uncover METTL3-mediated m6A modification as a novel regulatory axis in driving splicing dysregulation and contributing to aggressive CLL.METTL3 controls widespread splicing factor abundance via translational control of m6A-modified mRNA, contributes to RNA splicing dysregulation and disease progression in CLL, and serves as a potential therapeutic target in aggressive CLL. See related commentary by Janin and Esteller, p. 176. This article is highlighted in the In This Issue feature, p. 171.
Lem2 is essential for cardiac development by maintaining nuclear integrity
Authors: Jacob A Ross, Nathaly Arcos-Villacis, Edmund Battey, Cornelis Boogerd, Constanza Avalos Orellana, Emilie Marhuenda, Pamela Swiatlowska, Didier Hodzic, Fabrice Prin, Tim Mohun, Norman Catibog, Olga Tapia, Larry Gerace, Thomas Iskratsch, Ajay M Shah, Matthew J Stroud
Journal: Cardiovascular Research (2023)

Nuclear envelope integrity is essential for the compartmentalization of the nucleus and cytoplasm. Importantly, mutations in genes encoding nuclear envelope (NE) and associated proteins are the second highest cause of familial dilated cardiomyopathy. One such NE protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in the heart remains poorly understood.We generated mice in which Lem2 was specifically ablated either in embryonic cardiomyocytes (Lem2 cKO) or in adult cardiomyocytes (Lem2 iCKO) and carried out detailed physiological, tissue, and cellular analyses. High-resolution episcopic microscopy was used for three-dimensional reconstructions and detailed morphological analyses. RNA-sequencing and immunofluorescence identified altered pathways and cellular phenotypes, and cardiomyocytes were isolated to interrogate nuclear integrity in more detail. In addition, echocardiography provided a physiological assessment of Lem2 iCKO adult mice. We found that Lem2 was essential for cardiac development, and hearts from Lem2 cKO mice were morphologically and transcriptionally underdeveloped. Lem2 cKO hearts displayed high levels of DNA damage, nuclear rupture, and apoptosis. Crucially, we found that these defects were driven by muscle contraction as they were ameliorated by inhibiting myosin contraction and L-type calcium channels. Conversely, reducing Lem2 levels to ∼45% in adult cardiomyocytes did not lead to overt cardiac dysfunction up to 18 months of age.Our data suggest that Lem2 is critical for integrity at the nascent NE in foetal hearts, and protects the nucleus from the mechanical forces of muscle contraction. In contrast, the adult heart is not detectably affected by partial Lem2 depletion, perhaps owing to a more established NE and increased adaptation to mechanical stress. Taken together, these data provide insights into mechanisms underlying cardiomyopathy in patients with mutations in Lem2 and cardio-laminopathies in general.
Empagliflozin in heart failure with preserved ejection fraction with and without atrial fibrillation
Authors: Gerasimos Filippatos, Dimitrios Farmakis, Javed Butler, Faiez Zannad, João Pedro Ferreira, Anne Pernille Ofstad, Tomoko Iwata, Martina Brueckmann, Stuart J. Pocock, Milton Packer, Stefan D. Anker
Journal: European Journal of Heart Failure (2023)

Atrial fibrillation/flutter (AF) is common in heart failure (HF) with preserved left ventricular ejection fraction (LVEF) and associated with worse outcomes. Empagliflozin reduces cardiovascular death or HF hospitalizations and slows estimated glomerular filtration rate (eGFR) decline in patients with HF and LVEF >40%. We aimed to assess the efficacy and safety of empagliflozin in improving outcomes in patients with HF and LVEF >40% with and without AF.In this pre-defined secondary analysis of EMPEROR-Preserved, we compared the effects of empagliflozin versus placebo on the primary and secondary endpoints and safety outcomes, stratified by baseline AF, defined as AF reported in any electrocardiogram before empagliflozin initiation or in medical history. Among 5988 patients randomized, 3135 (52%) had baseline AF; these patients were older, with worse functional class, more previous HF hospitalizations and higher natriuretic peptides compared to those without AF (all p < 0.001). After a median of 26 months, empagliflozin reduced cardiovascular death or HF hospitalization compared to placebo to a similar extent in patients with and without AF (hazard ratio [HR] 0.78 [95% confidence interval 0.66-0.93] vs. 0.78 [0.64-0.95], interaction p = 0.96). Empagliflozin also reduced total HF hospitalizations (HR 0.73 [0.57-0.94] vs. 0.72 [0.54-0.95], interaction p = 0.94) and annual eGFR decline (difference = 1.368 vs. 1.372 ml/min/1.73 m2 /year, interaction p = 0.99) consistently in patients with and without AF. There was no increase in serious adverse events with empagliflozin versus placebo in patients with and without AF.In patients with HF and ejection fraction >40%, empagliflozin reduced the risk of serious HF events and slowed the eGFR decline regardless of baseline AF.